1. Field of the Invention
This invention relates generally to therapeutic painful stimuli such as electric shock pulses, and more particularly to the process of reducing the pain associated with these therapeutic painful stimuli by modifying a patient's pain perception and response using prepulse inhibition (PPI). Further, this invention relates to therapeutic electric shocks delivered to patients by implantable cardio-verter-defibrillators (ICDS) as treatment for atrial or ventricular arrhythmias. It relates particularly to reducing the pain associated with atrial defibrillation in a conscious patient.
2. Background Information
Implantable cardioverter-defibrillators (ICDs) deliver high-voltage electrical pulses (shocks) to terminate cardiac arrhythmias. This treatment is highly successful, but it is severely painful and may even stun a patient temporarily. Initially, painful and startling therapeutic shocks were considered acceptable only as a treatment of last resort. Because of this, ICD therapy was restricted to ventricular arrhythmias which were both life-threatening and refractory to all other therapies. Subsequently, however, ICDs have become first-line therapy for patients with a history of life-threatening ventricular arrhytmias and patients at risk for life-threatening ventricular arrhythmias. Controlled studies have shown that ICDs are superior to alternative therapy for specific groups of these patients. These studies are the Multicenter Automatic Defibrillator Implantation Trial (Moss et al, N Engl J Med 1996; 335:1933-1940) and the Antiarrythmics Versus Implantable Defibrillators Trial (Zipes et al, N Engl J Med 1997; 337:1576-1583).
As ICD therapy has been applied to larger numbers of patients with ventricular arrhythmias, more attention has been paid to the painful and startling nature of the therapeutic shocks and the psychological complications of this therapy. These factors limit patient acceptance of ICD treatment of arrhythmias in conscious patients. A significant fraction of patients report anxiety and fear of painful ICD shocks ((1) Dougherty, Psychological reactions and family adjustment in shock versus no shock groups after implantation of internal cardioverter defibrillator, Heart Lung 1995; 24:281-291--(2) Dunbar et al, Cognitive therapy for ventricular dysrhythmia patients, J Cardiovasc Nursing 1997; 12:33-44--(3) Luderitz et al, Patient acceptance of ICD devices: Changing attitudes, Am Heart J 1994; 127:1179-1184--(4) Morris et al, Psychiatric morbidity following implantation of the automatic ICD, Psychosomatics 1991; 32:58-64). Shocks correlate with anxiety, psychiatric morbidity and psychological distress in ICD recipients. In one study 87.5% of patients experienced "nervousness" after a shock and 12.5% experienced "terror" or "fear." Patients who have experienced large numbers of repetitive shocks frequently suffer from a form of post-traumatic stress disorder.
Recently, ICD therapy has been applied to treatment of atrial arrhythmias, particularly atrial fibrillation ((1) Lau et al, Initial clinical experience with an implantable human atrial defibrillator, PACE 1997; 20:220-225--(2) Timmersman et al, Early clinical experience with the Metrix automatic implantable atrial defibrillator, European Heart J 1997; 134). Although atrial fibrillation usually is not life-threatening, it is the most common arrhythmia requiring hospitalization in the United States. It causes potentially disabling symptoms of palpitations, shortness of breath, or chest pain and is an important cause of stroke.
The painful and startling nature of ICD shocks are considered a particular limitation for patient acceptance of ICD treatment of atrial fibrillation. It has been stated in recent published literature (Cooper et al, Internal atrial defibrillation in humans: Improved efficacy of biphasic waveforms and the importance of phase duration, Circulation 1997; 96:2693-2700) that the ultimate acceptance of a fully automatic atrial defibrillator will depend on the reduction of pain to acceptable levels.
To this end, present state-of-the-art holds that a primary method of reducing the pain associated with these shocks is to reduce the strength of the shock pulse as measured by energy or voltage. This method requires a significant decrease in the shock strength required to defibrillate with a success rate of 50%. This shock strength is known as the defibrillation threshold. Recent studies have focused on reducing the atrial defibrillation threshold by altering the shape (waveform) of the delivered shock pulse or the locations of the electrodes (electrode configuration) through which these shocks are applied. The fundamental hypothesis is that lowering of the defibrillation threshold will permit atrial defibrillation with weaker shocks and thereby decrease the pain associated with these shocks in patients.
The shock strength judged tolerable for defibrillation in conscious patients has differed in previous studies, but is generally in the range of 0.1-0.5 joules (J). Zipes (Zipes et al, Clinical transvenous cardioversion of recurrent life-threatening ventricular tachyarrhythmias: Low energy synchronized cardioversion of ventricular tachycardia and termination of ventricular fibrillation in patients using a catheter electrode, Am Heart J 1982; 103:789-794) reported that shocks of 0.5 J or less delivered between electrodes in the superior vena cava and right ventricle were tolerable for treatment of ventricular tachycardia. However, using the same electrode system, Perelman (Perelman et al, Assessment of prototype implantable cardioverter for ventricular tachycardia, Br Heart J 1984; 52:385-391) found that 3 of 9 patients reported severe discomfort at a shock strength of 0.1 J. Nathan (Nathan et al, Internal transvenous low energy cardioversion for the treatment of cardiac arrhythmias, Br Heart J 1984; 52:377) delivered transvenous shocks to 19 conscious patients for various atrial and ventricular arrhythmias. Fourteen of 19 patients described severe discomfort with shock strengths 0.5 J. Murgatroyd (Murgatroyd et al, Efficacy and tolerability of transvenous low energy cardioversion of paroxysmal atrial fibrillation in humans, J Am Coll Cardiol 1995; 25:1347-1353) determined the range of tolerable shock strengths for the most favorable electrode configuration for atrial defibrillation (right atrium to distal coronary sinus). Although the range of shock strengths tolerated without severe discomfort was 0.1 to 1.2 J, seven of 19 patients found even 0.1 J shocks intolerable. Using a different electrode system, Steinhaus (Steinhaus et al, Atrial defibrillation: are low energy shocks acceptable to patients? PACE 1996; 19:625) delivered shocks of 0.4 J and 2.0 J shocks in randomized order. Patients reported no difference in perceived pain between the two shock strengths. Both shock strengths were given discomfort scores of approximately 7 on a scale of 0-10.
However, Steinhaus found that the second shock was judged significantly more painful than the first shock, independent of shock strength. This observation is important because a strategy for reducing pain in defibrillation of arrhythmias which are not life-threatening (such as atrial fibrillation) contemplates clinical use of defibrillation shocks with strength near the defibrillation threshold. The hypothesis is that, even if multiple shocks are required to terminate the arrhythmia, multiple weaker shocks will be better tolerated than one strong shock. Steinhaus' data suggest that any clinical benefit in pain reduction achieved by delivering clinical defibrillation shocks with strength near the defibrillation threshold is likely to be offset by the increased discomfort associated with subsequent shocks as weak as 0.4 J.
Data reported for atrial defibrillation thresholds must be considered in the perspective of these reported values for tolerable shock strengths. Cooper (Cooper et al, Internal cardioversion of atrial fibrillation in sheep, Circulation 1993; 87:1673-1686) measured the atrial defibrillation threshold for multiple waveforms and electrode configurations in sheep. They showed that a specific biphasic waveform (3 ms phase 1 and 3 ms phase 2) and a specific electrode configuration (right atrial appendage to distal coronary sinus) resulted in the lowest atrial defibrillation threshold for the combinations of electrode configurations and waveforms tested (1.3.+-.0.4 J). However, use of this waveform and electrode configuration in humans with paroxysmal (intermittent) atrial fibrillation, the principal treatment population for atrial ICDs, resulted in atrial defibrillation thresholds approximately twice as high as in sheep. Johnson (Johnson et al, Circulation 1993; I 592) reported a value of 2.5.+-.1.4 J and Murgatroyd (Murgatroyd et al, J Am Coll Cardiol 1995; 25:1347-1353) reported a value of 2.2.+-.1.0 J. Therefore, the prior art does not teach a method sufficient for the reduction of a patient's perceived pain during atrial defibrillation shocks.
More recently, Cooper (Cooper et al, Internal cardioversion of atrial fibrillation: Marked reduction in defibrillation threshold with dual current pathways, Circulation 1997; 96:2693-2700) showed that sequential shocks delivered through two different sets of electrodes significantly decreased atrial defibrillation thresholds in sheep. The defibrillation threshold for this complex method (0.36.+-.0.13 J) was significantly lower than that of the best single-pathway method (1.3.+-.0.3 J). Since the average atrial defibrillation thresholds in sheep are approximately half that of the average atrial defibrillation thresholds for patients with paroxysmal atrial fibrillation, it was estimated that this newly determined method would provide average atrial defibrillation thresholds of slightly less than 1 J in patients. Thus, despite the additional complexity of the implant procedure and possible additional short and long-term morbidity associated with this new method, it is not likely to permit atrial defibrillation shocks without severe discomfort in the majority of patients. Therefore, this prior art does not teach a method sufficient for the significant reduction of a patient's perceived pain during atrial defibrillation. This prior art moreover requires the increased cost, surgical complexity, and risk associated with two additional electrodes.
The method and apparatus of U.S. Pat. No. 5,332,400 issued to Alferness discloses an implantable atrial defibrillator that provides a warning to a patient prior to delivery of an atrial shock pulse to cardiovert or defibrillate the patient's atrial arrhythmia. The atrial defibrillator applies a warning electrical shock to the patient's atria when the apparatus determines that the atria require cardioversion or defibrillation. The warning shock has an energy level lower than that required to treat the arrhythmia but high enough to be discerned by the patient without pain or other discomfort. The purpose of this warning is to provide sufficient time in advance of the therapeutic shock (in the range of 1 to 20 minutes) to afford a patient the opportunity to prepare for this painful and startling therapy. The Alferness method and apparatus demonstrate the limitation of the prior art to significantly reduce the extreme pain perceived by a patient when the defibrillation therapy is applied.
The method and apparatus of U.S. Pat. No. 5,439,481 issued to Adams discloses an implantable atrial and ventricular defibrillator that diagnoses atrial and ventricular arrhythmias, automatically treats the ventricular arrhythmias, but allows discretionary treatment of the atrial arrhythmias. Such discretionary control permits the patient to forego painful atrial defibrillation shocks based on a medical assessment that the atrial arrhythmia is not significantly dysfunctional and is amenable to less immediate and less urgent medical treatment. The Adams method and apparatus further demonstrate the limitation of the prior art to alleviate the extreme pain perceived by a patient when atrial defibrillation therapy is applied.
The method and apparatus of U.S. Pat. No. 5,630,834 issued to Bardy discloses an implantable atrial defibrillator that determines whether a patient is asleep prior to delivery of an atrial shock pulse. Defibrillation shocks that would be extremely painful to a conscious patient are delivered only when a patient is asleep. Bardy states that although numerous patents and applications attempt to optimize shock waveforms and electrode systems to reduce defibrillation thresholds (and therefore pain), the reliable accomplishment of low thresholds for all patients will remain a difficult and perhaps infeasible objective. This method may require a patient to remain in atrial fibrillation for many hours until the patient falls asleep. Thus it is not practical for some patients who become symptomatic shortly after the onset of atrial fibrillation or for patients with ventricular arrhythmias who typically require treatment as soon as possible after the onset of the arrhythmia. Further, some patients have reported being awakened from sleep by painful and startling ICD shocks. Thus, administration of shocks during sleep is painful in some patients. In addition, a patient's knowledge that he/she may be shocked while asleep may result in anticipatory anxiety that interferes with sleep. The Bardy method and apparatus further demonstrate the limitation of the prior art to significantly reduce the extreme pain perceived by a conscious patient when defibrillation therapy is applied.
We therefore describe a method and apparatus to significantly diminish or eliminate the perceived pain by reducing the perceived intensity of defibrillation shocks and by inhibiting the startle response associated with these shocks. The clinical basis for the present invention is the fundamental physiologic principal of PPI. As will be appreciated from a review of the background discussion and the detailed description of the preferred embodiments, the present invention overcomes the limitations and shortcomings of the prior art.
In the field of neurophysiologic and neuropsychiatric research, it has been long appreciated that the experienced intensity of a strong, abrupt stimulus, and the behavioral (startle) response to this stimulus can be diminished by delivering a weak stimulus 30-500 ms prior to the strong stimulus ((1) Cohen et al, Sensory magnitude estimation in the context of reflex modification, J Exper Psychology 1981; 7:1363-1370--(2) Swerdlow et al, "Neurophysiology and neuropharmacology of short lead interval startle modification," Chapter 6 of Startle Modification: Implications for Neuroscience, Cognitive Science, and Clinical Science, Dawson et al, Cambridge Univ Press, 1997). This physiologic suppression of the startle reflex is referred to as prepulse inhibition (PPI). PPI decreases both the motor (startle) response and the subject's perception of the intensity of the startling stimulus (pain). Normal human subjects consistently rate startling stimuli as significantly less intense if these stimuli are preceded by an appropriate weak prestimulus than if they were presented alone.
The neural circuitry responsible for the sensorimotor modulation of PPI has been studied extensively. These studies indicate that PPI reflects the activation of ubiquitous, "hard-wired," behavioral gating processes that are regulated by forebrain neural circuitry. PPI occurs in virtually all mammals, and can be elicited in humans and humans and experimental animals using near-identical stimuli to produce strikingly similar response patterns (Swerdlow et al, Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients, Arch Gen Psychiatry 1994; 51:139-154). The importance of these findings is that optimal stimulus parameters for PPI, and the neural substrates that regulate PPI, can be studied easily in animal models. This capability facilitates the application of PPI principles as disclosed in the preferred embodiments of the present invention.
In one preferred embodiment of the present invention, a single, low-voltage, short-duration pulse (the prepulse) precedes a high-voltage shock pulse. The time interval between the prepulse and the shock pulse is set between 30 to 500 ms. The specific time interval is determined by a testing method which identifies the optimal interval for PPI. The prepulse and therapeutic shocks may have arbitrary waveforms which are not necessarily identical. For example, these may include monophasic or biphasic capacitive-discharge pulses of the type presently used in ICDs, or a pulse waveform constructed specifically to reduce pain, such as a rounded, slow-rise time, or ascending ramp waveform (Mouchawar et al, Sural nerve sensory thresholds of defibrillation waveforms, J Amer Coll Card 1998; 31 (Suppl A): 373). At the time of implant of an atrial, ventricular, or dual-chamber ICD with the present invention incorporated therein, a physician first determines an appropriate electrode system for a given patient and the appropriate cardioversion or defibrillation energy setting for that patient and electrode system. The physician then adjusts the amplitude of the prepulse and intervening time interval between the prepulse and the therapeutic shock pulse so as to significantly reduce or eliminate the patient's perceived pain and startle response caused by the shock pulse. Typically, the shock strength required for cardioversion or defibrillation is determined while the patient is under the influence of a short-acting anesthetic. The prepulse amplitude and time interval are adjusted in the conscious patient after the effects of any short-acting anesthetic has dissipated. Alternatively, the prepulse amplitude and time interval are adjusted at a postoperative programming study.
It is important to note that defibrillation shocks are associated with a prominent startle responses in many patients. Studies of other types of startle responses demonstrate that startle responses are actually increased when warning stimuli preceded the startling stimuli at intervals (&gt;1 sec) that are adequate to evoke conscious anticipation of the startling stimulus (prepulse facilitation). Thus a "warning" prestimulus which is sufficiently early to evoke a conscious response prior to an ICD shock is likely to increase the shock-induced startle effect. ICD recipients report severe discomfort related specifically to the startling effects of defibrillating shocks. A long-delay "warning" prestimulus is a programmable option in some ICDs. This feature is rarely activated because patients experience anxiety during the anticipatory interval following the "warning" prestimulus. The present invention overcomes these problems by suppressing the painful "jolt" associated with the defibrillation-induced startle reflex, using automatic, preconscious mechanisms evoked during a time interval (30-500 ms) which is too short to stimulate anticipatory anxiety.
The methods and devices of the prior art that most nearly approach the novel features of the present invention, which uses PPI to reduce the perceived pain of therapeutic electrical stimuli delivered to a conscious patient, are, in fact, quite remote from it. Their marginal relevance can best be appreciated by a short, comparative description.
The method and apparatus of U.S. Pat. Nos. 5,314,448 and 5,366,485 issued to Kroll and Adams disclose electrical pretreatment to a ventricular fibrillating heart to permit the applied shock pulse to defibrillate the ventricles with less energy than may otherwise be required. Pretreatment pulses and the treatment shock are delivered through the same electrodes. The underlying hypothesis asserts that electrical pretreatment of a fibrillating heart is expected to achieve temporal organization of the ventricular cardiac cells, thereby diminishing the demands imposed on the defibrillation threshold for the defibrillating shock pulse. As will become apparent in the description of the preferred embodiments, the present invention differs significantly from this prior art. The concept of electrical pretreatment of a fibrillating heart to assist the defibrillating shock pulse by reducing its level of required energy through temporal cardiac organization is completely absent from the present invention.
The method and apparatus of U.S. Pat. No. 5,425,749 issued to Adams discloses the delivery of an electrical preemptive cardioversion shock to a patient determined to have a life-threatening arrhythmia such as ventricular fibrillation. The underlying hypothesis asserts that the shock strength required for defibrillation is directly related to the duration of fibrillation and that an electrical preemptive shock delivered as soon as possible following the onset of an arrhythmia will reduce the total energy requirements for cardioversion or defibrillation. The preemptive shock is thus delivered several seconds before the main cardioverting or defibrillating pulse. As will become apparent in the description of the preferred embodiments, the present invention differs significantly from this prior art. The concept of electrical preemptive cardioversion or defibrillation to quickly treat a patient and thereby to significantly reduce the size and energy requirements of a defibrillator is completely absent from the present invention.
Despite the need in the art for an ICD apparatus or methods which overcome the shortcomings and limitations of the prior art, none insofar as is known has been developed or proposed. Accordingly, it is an object of the present invention to provide an implantable atrial, ventricular, or dual-chamber ICD method and apparatus that applies the clinical science related to sensorimotor gating to reduce or eliminate the perceived intensity of, and startle response to, the ICD's shock pulse. The present invention reduces or eliminates the pain by delivering a timed prepulse that reduces the perceived intensity of the shock pulse, and inhibits the startle response to the shock pulse. There are no such teachings in the prior art.